| Autor: |
Kritikou JS; Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden., Dahlberg CI; Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden., Baptista MA; Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden., Wagner AK; Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden., Banerjee PP; Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA., Gwalani LA; Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA., Poli C; Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA., Panda SK; Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm 171 76, Sweden., Kärre K; Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden., Kaech SM; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA., Wermeling F; Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm 171 76, Sweden., Andersson J; Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm 171 76, Sweden., Orange JS; Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA., Brauner H; Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden., Westerberg LS; Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden. |
| Abstrakt: |
To kill target cells, natural killer (NK) cells organize signaling from activating and inhibitory receptors to form a lytic synapse. Wiskott-Aldrich syndrome (WAS) patients have loss-of-function mutations in the actin regulator WASp and suffer from immunodeficiency with increased risk to develop lymphoreticular malignancies. NK cells from WAS patients fail to form lytic synapses, however, the functional outcome in vivo remains unknown. Here, we show that WASp KO NK cells had decreased capacity to degranulate and produce IFNγ upon NKp46 stimulation and this was associated with reduced capacity to kill MHC class I-deficient hematopoietic grafts. Pre-treatment of WASp KO NK cells with IL-2 ex vivo restored degranulation, IFNγ production, and killing of MHC class I negative hematopoietic grafts. Moreover, WASp KO mice controlled growth of A20 lymphoma cells that naturally produced IL-2. WASp KO NK cells showed increased expression of DNAM-1, LAG-3, and KLRG1, all receptors associated with cellular exhaustion and NK cell memory. NK cells isolated from WAS patient spleen cells showed increased expression of DNAM-1 and had low to negative expression of CD56, a phenotype associated with NK cells exhaustion. Finally, in a cohort of neuroblastoma patients we identified a strong correlation between WASp, IL-2, and patient survival. |
